Sarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, Institute of Cancer Research, London, UK.
Glioma Team, Divisions of Molecular Pathology and Cancer Therapeutics, Institute of Cancer Research, London, UK.
J Pathol. 2018 Feb;244(2):242-253. doi: 10.1002/path.5008. Epub 2018 Jan 10.
Testicular germ cell tumours (TGCTs) are the most frequent malignancy and cause of death from solid tumours in the 20- to 40-year age group. Although most cases show sensitivity to cis-platinum-based chemotherapy, this is associated with long-term toxicities and chemo-resistance. Roles for receptor tyrosine kinases other than KIT are largely unknown in TGCT. We therefore conducted a phosphoproteomic screen and identified the insulin growth factor receptor-1 (IGF1R) as both highly expressed and activated in TGCT cell lines representing the nonseminomatous subtype. IGF1R was also frequently expressed in tumour samples from patients with nonseminomas. Functional analysis of cell line models showed that long-term shRNA-mediated IGF1R silencing leads to apoptosis and complete ablation of nonseminoma cells with active IGF1R signalling. Cell lines with high levels of IGF1R activity also showed reduced AKT signalling in response to decreased IGF1R expression as well as sensitivity to the small-molecule IGF1R inhibitor NVP-AEW541. These results were in contrast to those in the seminoma cell line TCAM2 that lacked IGF1R signalling via AKT and was one of the two cell lines least sensitive to the IGF1R inhibitor. The dependence on IGF1R activity in the majority of nonseminomas parallels the known role of IGF signalling in the proliferation, migration, and survival of primordial germ cells, the putative cell of origin for TGCT. Upregulation of IGF1R expression and signalling was also found to contribute to acquired cisplatin resistance in an in vitro nonseminoma model, providing a rationale for targeting IGF1R in cisplatin-resistant disease. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
睾丸生殖细胞肿瘤（TGCT）是 20 至 40 岁年龄组中最常见的恶性肿瘤和实体肿瘤死亡原因。尽管大多数病例对顺铂为基础的化疗敏感，但这与长期毒性和化疗耐药有关。除 KIT 外，受体酪氨酸激酶在 TGCT 中的作用在很大程度上尚不清楚。因此，我们进行了磷酸蛋白质组筛选，发现胰岛素生长因子受体-1（IGF1R）在代表非精原细胞瘤亚型的 TGCT 细胞系中高度表达和激活。IGF1R 在非精原细胞瘤患者的肿瘤样本中也经常表达。细胞系模型的功能分析表明，长期 shRNA 介导的 IGF1R 沉默导致凋亡和具有活性 IGF1R 信号的非精原细胞瘤细胞完全消融。具有高水平 IGF1R 活性的细胞系在 IGF1R 表达减少时也显示 AKT 信号减少，并且对小分子 IGF1R 抑制剂 NVP-AEW541 敏感。这些结果与缺乏 AKT 途径中 IGF1R 信号的精原细胞瘤细胞系 TCAM2 的结果相反，TCAM2 是对 IGF1R 抑制剂最不敏感的两种细胞系之一。大多数非精原细胞瘤对 IGF1R 活性的依赖性与 IGF 信号在原始生殖细胞增殖、迁移和存活中的已知作用相平行，原始生殖细胞是 TGCT 的起源细胞。在体外非精原细胞瘤模型中，IGF1R 表达和信号的上调也被发现有助于获得性顺铂耐药，为针对顺铂耐药疾病中的 IGF1R 提供了依据。
